Hypersensitivity to clozapine or any component of the formulation; history of agranulocytosis or severe granulocytopenia with clozapine; uncontrolled epilepsy, severe central nervous system depression or comatose state; paralytic ileus; myeloproliferative disorders or use with other agents which have a well-known risk of agranulocytosis or bone marrow suppression Canadian labeling: Additional Contraindications (not in U.S. labeling): Active hepatic disease associated with nausea, anorexia, or jaundice; progressive hepatic disease or hepatic failure; severe renal impairment; severe cardiac disease (eg, myocarditis); patients unable to undergo blood testing

Warnings / Precautions Drug

Boxed warnings:• Agranulocytosis: See “Concerns related to adverse effects” below.• Cardiovascular events: See “Concerns related to adverse effects” below.• Dementia: See “Disease-related concerns” below.• Orthostatic hypotension: See “Concerns related to adverse effects” below.• Seizures: See “Concerns related to adverse effects” below.Concerns related to adverse effects:• Agranulocytosis: [U.S. Boxed Warning]: Significant risk of agranulocytosis, potentially life-threatening. Therapy should not be initiated in patients with WBC <3500 cells/mm3 or ANC <2000 cells/mm3 or history of myeloproliferative disorder. WBC testing should occur periodically on an on-going basis (see prescribing information for monitoring details) to ensure that acceptable WBC/ANC counts are maintained. Initial episodes of moderate leukopenia or granulopoietic suppression confer up to a 12-fold increased risk for subsequent episodes of agranulocytosis. WBCs must be monitored weekly for at least 4 weeks after therapy discontinuation or until WBC is ≥3500/mm3 and ANC is ≥2000/mm3. Use with caution in patients receiving other marrow suppressive agents. Eosinophilia has been reported to occur with clozapine. Interrupt therapy for eosinophil count >4000/mm3. May resume therapy when eosinophil count <3000/mm3. (Note: The Canadian labeling recommends discontinuing therapy for eosinophil count >3000/mm3; may resume therapy when eosinophil count <1000/mm3). Due to the significant risk of agranulocytosis, it is strongly recommended that a patient must fail at least two trials of other primary medications for the treatment of schizophrenia (of adequate dose and duration) before initiating therapy with clozapine.• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. • Cardiovascular events: Myocarditis, pericarditis, pericardial effusion, cardiomyopathy, and HF have also been associated with clozapine. [U.S. Boxed Warning]: Fatalities due to myocarditis have been reported; highest risk in the first month of therapy, however, later cases also reported. Myocarditis or cardiomyopathy should be considered in patients who present with signs/symptoms of heart failure (dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema), chest pain, palpitations, new electrocardiographic abnormalities (arrhythmias, ST-T wave abnormalities), or unexplained fever. Patients with tachycardia during the first month of therapy should be closely monitored for other signs of myocarditis. Discontinue clozapine if myocarditis is suspected; do not rechallenge in patients with clozapine-related myocarditis. The reported rate of myocarditis in clozapine-treated patients appears to be 17-322 times greater than in the general population. Clozapine should be discontinued in patients with confirmed cardiomyopathy unless benefit clearly outweighs risk. • Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of atypical antipsychotics in elderly patients with dementia-related psychosis.• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (eg, Alzheimer's disease). • Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients.• Fever: Benign transient temperature elevation (>100.4°F) may occur; peaking within the first 3 weeks of treatment. Rule out infection, agranulocytosis, and neuroleptic malignant syndrome (NMS) in patients presenting with fever.• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. • Neuroleptic malignant syndrome (NMS): Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.• Orthostatic hypotension: [U.S. Boxed Warning]: May cause orthostatic hypotension (with or without syncope); generally occurs more frequently with initial titration and in association with rapid dose increases. Use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). • Sedation: May be moderate to highly sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving general anesthesia. • Seizures: [U.S. Boxed Warning]: Seizures have been associated with clozapine use in a dose-dependent manner; use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.• Tachycardia: May cause tachycardia (including sustained); sustained tachycardia is not limited to a reflex response to orthostatic hypotension, and is present in all positions.• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.• Thromboembolism: Rare cases of thromboembolism, including pulmonary embolism and stroke resulting in fatalities, have been associated with clozapine in patients with cardiovascular disease.• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.Disease-related concerns:• Cardiovascular disease: Use with caution in patients with cardiovascular disease; gradually increase dose.• Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Clozapine is not approved for the treatment of dementia-related psychosis.• Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade. Screening is recommended.• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; monitor hepatic function regularly. Hepatitis has been reported as a consequence of therapy. Discontinuation of therapy may be necessary with significant elevations in liver function tests; may reinitiate with close monitoring and if values return to normal.• Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade.• Pulmonary disease: Use with caution; gradually increase dose.• Renal impairment: Use with caution in patients with renal impairment.Concurrent drug therapy issues:• Benzodiazepines: Concurrent use with benzodiazepines may increase the risk of severe cardiopulmonary reactions. Special populations:• Elderly: The elderly are more susceptible to adverse effects (including agranulocytosis, cardiovascular, anticholinergic, and tardive dyskinesia). • Smokers: Clozapine levels may be lower in patients who smoke. Smoking cessation may cause toxicity in a patient stabilized on clozapine. Monitor change in smoking patterns. Dosage form specific issues:• Phenylalanine: FazaClo® oral disintegrating tablets contain phenylalanine.Other warnings/precautions: • Abrupt discontinuation: Medication should not be stopped abruptly; taper off over 1-2 weeks. If conditions warrant abrupt discontinuation (leukopenia, myocarditis, cardiomyopathy), monitor patient for psychosis and cholinergic rebound (headache, nausea, vomiting, diarrhea).

B Pregnancy Implications Teratogenic effects were not seen in animal studies. Clozapine crosses the placenta and can be detected in the fetal blood and amniotic fluid. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. Healthcare providers are encouraged to enroll women 18-45 years of age exposed to clozapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388). Women with amenorrhea associated with use of other antipsychotic agents may return to normal menstruation when switching to clozapine therapy. Reliable contraceptive measures should be employed by women of childbearing potential switching to clozapine therapy.